Synthesis of 14-Azacamptothecin, a Water-Soluble Topoisomerase I Poison

2005 ◽  
Vol 7 (5) ◽  
pp. 835-837 ◽  
Author(s):  
Nicolas J. Rahier ◽  
Kejun Cheng ◽  
Rong Gao ◽  
Brian M. Eisenhauer ◽  
Sidney M. Hecht
Keyword(s):  
Topoisomerase I ◽  
Water Soluble

scholarly journals In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2817-2828 ◽  
Author(s):  
FM Uckun ◽  
CF Stewart ◽  
G Reaman ◽  
LM Chelstrom ◽  
J Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Topoisomerase I ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Water Soluble ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
B Lineage

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.

14-Azacamptothecin:  A Potent Water-Soluble Topoisomerase I Poison

2005 ◽  
Vol 127 (3) ◽  
pp. 838-839 ◽  
Author(s):  
Kejun Cheng ◽  
Nicolas J. Rahier ◽  
Brian M. Eisenhauer ◽  
Rong Gao ◽  
S. J. Thomas ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Water Soluble

Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I

1995 ◽  
Vol 38 (3) ◽  
pp. 395-401 ◽  
Author(s):  
Michael J. Luzzio ◽  
Jeffrey M. Besterman ◽  
David L. Emerson ◽  
Michael G. Evans ◽  
Karen Lackey ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Topoisomerase I ◽  
Water Soluble ◽  
Derivatives Of ◽  
Specific Inhibitors

scholarly journals Comparison of In Vitro Activities of Camptothecin and Nitidine Derivatives against Fungal and Cancer Cells

1999 ◽  
Vol 43 (12) ◽  
pp. 2862-2868 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Shih-Fong Chen ◽  
Daniel Von Hoff ◽  
Christine C. Dykstra ◽  
Mansukh C. Wani ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Mammalian Cells ◽  
Topoisomerase I ◽  
Active Form ◽  
Antifungal Drugs ◽  
Water Soluble ◽  
Yeast Cells ◽  
Original Structure ◽  
Camptothecin Analogs

ABSTRACT The activities of a series of camptothecin and nitidine derivatives that might interact with topoisomerase I were compared against yeast and cancer cell lines. Our findings reveal that structural modifications to camptothecin derivatives have profound effects on the topoisomerase I-drug poison complex in cells. Although the water-soluble anticancer agents topotecan and irinotecan are less active than the original structure, camptothecin, other derivatives or analogs with substitutions that increase compound solubility have also increased antifungal activities. In fact, a water-soluble prodrug appears to penetrate into the cell and release its active form; the resulting effect in complex with Cryptococcus neoformanstopoisomerase I is a fungicidal response and also potent antitumor activity. Some of the compounds that are not toxic to wild-type yeast cells are extremely toxic to the yeast cells when the C. neoformans topoisomerase I target is overexpressed. With the known antifungal mechanism of a camptothecin-topoisomerase I complex as a cellular poison, these findings indicate that drug entry may be extremely important for antifungal activity. Nitidine chloride exhibits antifungal activity against yeast cells through a mechanism(s) other than topoisomerase I and appears to be less active than camptothecin analogs against tumor cells. Finally, some camptothecin analogs exhibit synergistic antifungal activity against yeast cells in combination with amphotericin B in vitro. Our results suggest that camptothecin and/or nitidine derivatives can exhibit potent antifungal activity and that the activities of camptothecin derivatives with existing antifungal drugs may be synergistic against pathogenic fungi. These new compounds, which exhibit potent antitumor activities, will likely require further structural changes to find more selective activity against fungal versus mammalian cells to hold promise as a new class of antifungal agents.

Water Soluble Inhibitors of Topoisomerase I:  Quaternary Salt Derivatives of Camptothecin

1996 ◽  
Vol 39 (3) ◽  
pp. 713-719 ◽  
Author(s):  
Karen Lackey ◽  
Daniel D. Sternbach ◽  
Dallas K. Croom ◽  
David L. Emerson ◽  
Michael G. Evans ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Quaternary Salt ◽  
Water Soluble ◽  
Derivatives Of

Water-Soluble Camptothecin Derivatives that Are Intrinsic Topoisomerase I Poisons

2004 ◽  
Vol 6 (3) ◽  
pp. 321-324 ◽  
Author(s):  
Nicolas J. Rahier ◽  
Brian M. Eisenhauer ◽  
Rong Gao ◽  
Shannon H. Jones ◽  
Sidney M. Hecht
Keyword(s):  
Topoisomerase I ◽  
Water Soluble

Synthesis of novel water-soluble 7-(aminoacylhydrazono)-formyl camptothecins with potent inhibition of DNA topoisomerase I☆

1994 ◽  
Vol 2 (12) ◽  
pp. 1397-1402 ◽  
Author(s):  
Hui-Kang Wang ◽  
Su-Yin Liu ◽  
Kou-Maou Hwang ◽  
Glen Taylor ◽  
Kuo-Hsiung Lee
Keyword(s):  
Topoisomerase I ◽  
Water Soluble ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase ◽  
Potent Inhibition

Randomized Trial of Two Intravenous Schedules of the Topoisomerase I Inhibitor Liposomal Lurtotecan in Women With Relapsed Epithelial Ovarian Cancer: A Trial of the National Cancer Institute of Canada Clinical Trials Group

2005 ◽  
Vol 23 (9) ◽  
pp. 1859-1866 ◽  
Author(s):  
Graham G. Dark ◽  
A. Hilary Calvert ◽  
Robert Grimshaw ◽  
Christopher Poole ◽  
Ken Swenerton ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
Objective Response ◽  
Statistical Design ◽  
Primary Outcome Measure ◽  
Water Soluble ◽  
Topoisomerase I Inhibitor ◽  
Peritoneal Cancer ◽  
Randomized Design

Purpose Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. Patients and Methods Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m2/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m2/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. Results Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. Conclusion The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.

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